title: A phase II and biomarker study of ramucirumab, a human monoclonal antibody targeting the VEGF receptor-2, as first-line monotherapy in patients with advanced hepatocellular cancer.
abstract: OBJECTIVE
  To assess the efficacy and safety of the anti-VEGF receptor-2 (VEGFR-2) antibody ramucirumab as first-line therapy in patients with advanced hepatocellular carcinoma and explore potential circulating biomarkers.
  
  
  METHODS
  Adults with advanced hepatocellular carcinoma and no prior systemic treatment received ramucirumab 8 mg/kg every two weeks until disease progression or limiting toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR) and overall survival (OS). Circulating biomarkers were evaluated before and after ramucirumab treatment in a subset of patients.
  
  
  RESULTS
  Forty-two patients received ramucirumab. Median PFS was 4.0 months [95% confidence interval (CI), 2.6-5.7], ORR was 9.5% (95% CI, 2.7-22.6; 4/42 patients had a partial response), and median OS was 12.0 months (95% CI, 6.1-19.7). For patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease, median OS was 4.4 months (95% CI, 0.5-9.0) for patients with Child-Pugh B cirrhosis versus 18.0 months (95% CI, 6.1-23.5) for patients with Child-Pugh A cirrhosis. Treatment-related grade ≥ 3 toxicities included hypertension (14%), gastrointestinal hemorrhage and infusion-related reactions (7% each), and fatigue (5%). There was one treatment-related death (gastrointestinal hemorrhage). After treatment with ramucirumab, there was an increase in serum VEGF and placental growth factor (PlGF) and a transient decrease in soluble VEGFR-2.
  
  
  CONCLUSIONS
  Ramucirumab monotherapy may confer anticancer activity in advanced hepatocellular carcinoma with an acceptable safety profile. Exploratory biomarker studies showed changes in circulating VEGF, PlGF, and sVEGFR-2 that are consistent with those seen with other anti-VEGF agents.
authors.affiliation: Authors' Affiliations: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; David Geffen School of Medicine, University of California, Los Angeles, California; Northwestern University Feinberg School of Medicine, Chicago Illinois; East Jefferson General Hospital, Metairie, Louisiana; Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; ImClone Systems, a wholly-owned subsidiary of Eli Lilly and company, Bridgewater, New Jersey; Eli Lilly and Company, Indianapolis, Indiana; and Lahey Hospital and Medical Center, Tufts University School of Medicine, Burlington, Massachusetts.
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finn
authors.forename: Mary
authors.initials: M
authors.lastname: Mulcahy
authors.forename: Jayne
authors.initials: J
authors.lastname: Gurtler
authors.forename: Weijing
authors.initials: W
authors.lastname: Sun
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Schwartz
authors.forename: Rita P
authors.initials: RP
authors.lastname: Dalal
authors.forename: Adarsh
authors.initials: A
authors.lastname: Joshi
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Hozak
authors.forename: Yihuan
authors.initials: Y
authors.lastname: Xu
authors.forename: Marek
authors.initials: M
authors.lastname: Ancukiewicz
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.forename: Francis W
authors.initials: FW
authors.lastname: Nugent
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.forename: Keith
authors.initials: K
authors.lastname: Stuart
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000097:blood; D016016:Proportional Hazards Models; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000097:blood; D000096662:Ramucirumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000096662:Ramucirumab; C000608036:PGF protein, human; C467484:VEGFA protein, human